Amyloidosis includes a variety of diseases characterized by an accumulation of amyloid material in the organs or tissues of the body. This accumulation can impair vital functions. Diseases associated with amyloidosis include Alzheimer's disease (AD), Down's Syndrome, progressive supranuclear palsy, multiple sclerosis, and Adult Onset Diabetes. Localized amyloidosis is associated with cognitive decline (senile cerebral amyloidosis; Alzheimer's), heart disease (senile cardiac amyloidosis), endocrine tumors (thyroid cancer), and Adult Onset Diabetes, diseases which are found in millions of Americans.
A number of impairments specific to amyloid deposits in the brain are linked with the deposition of the peptide, Aβ peptide (amyloid-β peptide). Neurological diseases associated with Aβ peptide deposition include Alzheimer's, Lewy body dementia, Down's Syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type), and the Guamanian Parkinsonism-Dementia. Aβ peptide plaques also occur in persons who have experienced head trauma and critical coronary disease.
The most common disease related to cognitive decline or dementia is Alzheimer's Disease (AD). This condition is characterized by neuronal loss, neurofibrillary tangles, and neuritic plaques comprised of Aβ peptide. Due to the nature of cerebral amyloidosis, diagnosis of Alzheimer's before death is difficult and the development of therapies or other treatments for Alzheimer's have been elusive. Many proposed therapies are unable to cross the blood-brain barrier in amounts necessary for effective treatment.
It is currently believed that amyloid plaques in the brain are predominantly composed of Aβ peptide, a 4 kD protein, 39–43 amino acids long. Aβ peptide is expressed by a gene located on chromosome 21 and is derived by proteolytic cleavage from the interior of a much larger (770 residue) cell protein, amyloid precursor protein (APP). After excision, Aβ peptide is polymerized into amyloid filaments, which in turn aggregate into amyloid plaque deposits. In the brain, these filaments and aggregates are toxic to neurons and are thought to relate to the causative symptoms associated with AD.
The inability to examine amyloid deposition of AD in patients before death impedes the ability of researchers to study AD and develop effective therapies targeted at preventing or reversing amyloid plaque formation on the brain. Damage to CNS neurons due to AD begins years before clinical symptoms are evident. Prevention of amyloidosis in the brain would prevent the development of AD. A similar approach to preventing or treating amylin plaque formation in Adult Onset Diabetes patients would also be beneficial.
Other investigations have identified a set of mutations that cause familial Alzheimer's disease (FAD), in an autosomal dominant manner. All known FAD mutations increase either the absolute or relative production of the most pathogenic Aβ peptide with 42 amino acids. These mutations arise either in the APP gene itself, affecting the target sites in the APP where proteolytic cleavage occurs, or in one of two presenilin genes, the protein products which directly or, more probably, indirectly affect APP processing. The early step of AD excision is followed by the polymerisation of the peptide to amyloid filaments, which in turn aggregate into the visible amyloid plaque deposits that characterize the brains of individuals with AD. These filaments, or possibly intermediate protofilamants, are toxic to neurons and are thought to lead to neurofibrillary tangles, synapse loss, and neurodegeneration that underlie the decline of cognitive functions in Alzheimer's patients.
In addition to the production of the Aβ peptide (amyloid-β peptide), other important steps are involved in the pathogenic pathway leading to AD. Genetic and biochemical studies both assign a key role to a set of auxiliary proteins that function as “pathological chaperones”. One such protein is the anti-protease, anti-chyrmotrypsin, and another is the lipid transport protein, apolipoprotein F, particularly its E4 allelic form. Both of these proteins promote the formation and maturation of Alzheimer's plaques with their core of Aβ filaments. Specifically, the pathological chaperones can be demonstrated in vitro to accelerate the polymerisation of Aβ into neurotoxic amyloid filaments, and experiments with transgenic mice support their role in promoting amyloid formation in vivo. Both proteins are minor components of the amyloid deposits, and are evidently produced as part of an inflammation reaction that arises in response to the initial diffuse deposition of Aβ peptide.
What is needed are methods and compositions for diagnosis and treatment of amyloid-associated diseases.